Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter to the Editor
  • Published:

Novel TKI-resistant BCR-ABL1 gatekeeper residue mutations retain in vitro sensitivity to axitinib

Leukemia volume 30, pages 1405–1409 (2016)Cite this article

Subjects

Tyrosine kinase inhibitor (TKI) resistance due to acquired secondary kinase domain (KD) mutations in BCR-ABL1 represents a common clinically encountered problem in patients with chronic myeloid leukemia (CML). The prototypic ABL1 TKI imatinib is vulnerable to a large number of resistance-conferring secondary KD mutations.1 Clinical management of imatinib-resistant disease has been successfully guided by in vitro studies of mutant sensitivities to alternative TKIs, which are largely predictive of clinical responsiveness.2

Kinase ‘gatekeeper’ residues (T315 in BCR-ABL1) restrict access to a deeper hydrophobic pocket within the KD and mutations at this residue are problematic for numerous inhibitors of pathologically activated kinases (KIT, FIP1L1-PDGFRB, EGFR, EML4-ALK and FLT3-ITD). These substitutions can impact ATP affinity, affect the conformation of the kinase activation loop and alter substrate preference. In BCR-ABL1, an isoleucine substitution has been the most commonly reported and problematic gatekeeper mutation (T315I). Crystal structures have demonstrated that imatinib3 and all approved second-generation ABL1 TKIs (dasatinib,4 nilotinib5 and bosutinib6) make critical contact with the T315 residue, providing structural rationale for the vulnerability of these TKIs to the T315I mutation. The third-generation ABL1 TKI ponatinib was rationally designed to retain activity against the T315I substitution7 and represents the only approved TKI option for BCR-ABL1/T315I mutant CML. Although highly active in this setting, ponatinib is associated with a substantial risk of thrombotic events, and alternative strategies appear necessary for safer long-term management of T315I-associated CML. Ponatinib is considered a ‘pan-BCR-ABL’ inhibitor because of its invulnerability to mutations that may arise as a consequence of single-nucleotide substitutions. However, select ‘compound’ mutations (two or more amino-acid substitutions or a single-amino-acid substitution if both nucleotide changes occur within the same codon) can confer ponatinib resistance in vitro and clinically.8 With the increasing prevalence of CML worldwide, the extensive use of sequential ABL1 TKI therapy and the ability to more effectively suppress mutants that arise from a single-nucleotide change, compound mutations will likely be increasingly encountered in the clinical management of CML.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

References

  1. Soverini S, Colarossi S, Gnani A, Rosti G, Castagnetti F, Poerio A et al. Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of Philadelphia-positive patients: by the GIMEMA Working Party on Chronic Myeloid Leukemia. Clin Cancer Res 2006; 12: 7374–7379.

    Article  CAS  Google Scholar 

  2. Weisberg E, Manley PW, Cowan-Jacob SW, Hochhaus A, Griffin JD . Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia. Nat Rev Cancer 2007; 7: 345–356.

    Article  CAS  Google Scholar 

  3. Schindler T, Bornmann W, Pellicena P, Miller WT, Clarkson B, Kuriyan J . Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science 2000; 289: 1938–1942.

    Article  CAS  Google Scholar 

  4. Tokarski JS, Newitt JA, Chang CY, Cheng JD, Wittekind M, Kiefer SE et al. The structure of dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants. Cancer Res 2006; 66: 5790–5797.

    Article  CAS  Google Scholar 

  5. Nagar B, Bornmann WG, Pellicena P, Schindler T, Veach DR, Miller WT et al. Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571). Cancer Res 2002; 62: 4236–4243.

    CAS  PubMed  Google Scholar 

  6. Levinson NM, Boxer SG . Structural and spectroscopic analysis of the kinase inhibitor bosutinib and an isomer of bosutinib binding to the Abl tyrosine kinase domain. PLoS One 2012; 7: e29828.

    Article  CAS  Google Scholar 

  7. O'Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 2009; 16: 401–412.

    Article  CAS  Google Scholar 

  8. Zabriskie MS, Eide CA, Tantravahi SK, Vellore NA, Estrada J, Nicolini FE et al. BCR-ABL1 compound mutations combining key kinase domain positions confer clinical resistance to ponatinib in Ph chromosome-positive leukemia. Cancer Cell 2014; 26: 428–442.

    Article  CAS  Google Scholar 

  9. Davis MI, Hunt JP, Herrgard S, Ciceri Pietro, Wodicka LM, Pallares G et al. Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol 2011; 29: 1046–1051.

    Article  CAS  Google Scholar 

  10. Pemovska T, Johnson E, Kontro M, Repasky GA, Chen J, Wells P et al. Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation. Nature 2015; 519: 102–105.

    Article  CAS  Google Scholar 

  11. Shah NP, Skaggs BJ, Branford S, Hughes TP, Nicoll JM, Paquette RL et al. Sequential ABL kinase inhibitor therapy selects for compound drug-resistant BCR-ABL mutations with altered oncogenic potency. J Clini Invest 2007; 117: 2562–2569.

    Article  CAS  Google Scholar 

  12. Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001; 293: 876–880.

    Article  CAS  Google Scholar 

  13. How GF, Müller MC, Lim LC . Acquistion of the novel ABL kinase domain mutation T315L in a relapsed Philadelphia-positive acute lymphoblastic leukemia patient. Leuk Res 2012; 36: e20–e21.

    Article  CAS  Google Scholar 

  14. Al-Ali H-K, Heinrich MC, Lange T, Krahl R, Mueller M, Müller C et al. High incidence of BCR-ABL kinase domain mutations and absence of mutations of the PDGFR and KIT activation loops in CML patients with secondary resistance to imatinib. Hematol J 2004; 5: 55–60.

    Article  CAS  Google Scholar 

  15. Redaelli S, Mologni L, Rostagno R, Piazza R, Magistroni V, Ceccon M et al. Three novel patient-derived BCR/ABL mutants show different sensitivity to second and third generation tyrosine kinase inhibitors. Am J Hematol 2012; 87: E125–E128.

    Article  CAS  Google Scholar 

  16. Zhou T, Commodore L, Huang W-S, Wang Y, Thomas M, Keats J et al. Structural mechanism of the pan-BCR-ABL inhibitor ponatinib (AP24534): Lessons for overcoming kinase inhibitor resistance. Chem Biol Drug Des 2011; 77: 1–11.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

NPS and CCS were supported by the Leukemia & Lymphoma Society, and wish to acknowledge the generosity of Arthur Kern and the Edward S Ageno family. NPS has received funding for the conduct of research from Bristol–Myers Squibb, ARIAD and Pfizer.

Author information

Author notes

  1. E A Lasater and E S Massi: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Hematology/Oncology, University of California, San Francisco, CA, USA

    E A Lasater, E S Massi, J Politi, S K Tan, C C Smith & N P Shah

  2. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA

    A Stecula & A Sali

  3. Department of Laboratory Medicine, University of California, San Francisco, CA, USA

    M Gunthorpe & F Chehab

  4. Annadel Medical Group, Santa Rosa, CA, USA

    J P Holmes

  5. Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA

    A Sali

  6. California Institute for Quantitative Biosciences, University of California, San Francisco, CA, USA

    A Sali

  7. Helen Diller Comprehensive Cancer Center, University of California, San Francisco, CA, USA

    N P Shah

Authors
  1. E A Lasater
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E S Massi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Stecula
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Politi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S K Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C C Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Gunthorpe
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J P Holmes
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. F Chehab
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. A Sali
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. N P Shah
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to N P Shah.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lasater, E., Massi, E., Stecula, A. et al. Novel TKI-resistant BCR-ABL1 gatekeeper residue mutations retain in vitro sensitivity to axitinib. Leukemia 30, 1405–1409 (2016). https://doi.org/10.1038/leu.2015.303

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2015.303

Search

Advanced search

Quick links